Drug sensitivity testing on patient-derived sarcoma cells predicts patient response to treatment and identifies c-Sarc inhibitors as active drugs for translocation sarcomas

Abstract

Background Heterogeneity and low incidence comprise the biggest challenge in sarcoma diagnosis and treatment. Chemotherapy, although efficient for some sarcoma subtypes, generally results in poor clinical responses and is mostly recommended for advanced disease. Specific genomic aberrations have been identified in some sarcoma subtypes but few of them can be targeted with approved drugs. Methods We cultured and characterised patient-derived sarcoma cells and evaluated their sensitivity to 525 anti-cancer agents including both approved and non-approved drugs. In total, 14 sarcomas and 5 healthy mesenchymal primary cell cultures were studied. The sarcoma biopsies and derived cells were characterised by gene panel sequencing, cancer driver gene expression and by detecting specific fusion oncoproteins in situ in sarcomas with translocations. Results Soft tissue sarcoma cultures were established from patient biopsies with a success rate of 58%. The genomic profile and drug sensitivity testing on these samples helped to identify targeted inhibitors active on sarcomas. The cSrc inhibitor Dasatinib was identified as an active drug in sarcomas carrying chromosomal translocations. The drug sensitivity of the patient sarcoma cells ex vivo correlated with the response to the former treatment of the patient. Conclusions Our results show that patient-derived sarcoma cells cultured in vitro are relevant and practical models for genotypic and phenotypic screens aiming to identify efficient drugs to treat sarcoma patients with poor treatment options.

Ewing Sarcoma—Diagnosis, Treatment, Clinical Challenges and Future Perspectives

“…While important, there are widely recognized caveats in the use of long-established cell lines growing on rigid substrates, including genetic drift of cell lines under long-term culture [ 372 ] and non-physiologic response to 2D culture on plastic or glass. Several methods have been adopted to address these caveats, including analysis of primary patient-derived lines [ 373 ], and the development of 3D spheroid and organoid models [ 374 , 375 ]. Emphasizing the importance of modeling the tumor environment, Santoro and co-workers showed that culture of EwS cells on 3D scaffolds within a flow perfusion bioreactor promoted insulin-like growth factor-1 (IGF1) production and revealed shear stress-dependent resistance to an IGF-1R inhibitor [ 376 ].…”

Overactive IGF1/Insulin Receptors and NRASQ61R Mutation Drive Mechanisms of Resistance to Pazopanib and Define Rational Combination Strategies to Treat Synovial Sarcoma

“…Taken together, these data underline the relevance of molecular and immunohistochemical interrogation for resistance-associated targets to improve SS treatment outcome by patient-specific pazopanib-based combination therapies. Moreover, implementation of the use of patient-derived ex vivo systems (e.g., primary cell cultures, 3D systems) is also expected to provide an opportunity to discover new mechanisms of drug resistance and improve personalized treatments [69,70].…”

Feasibility study of using high‐throughput drug sensitivity testing to target recurrent glioblastoma stem cells for individualized treatment

“…The selective drug sensitivity score (sDSS) of each compound was calculated using two independent reference databases; (i) our in‐house GBM drug screening database (up to n = 18 GBMs tested for drug sensitivity to the drug collection) and (ii) the FIMM database of drug sensitivity to normal bone marrow cells from healthy donors (n = 5). Control samples of normal bone marrow cells were obtained from informed and consenting donors, and the sampling was approved by the institutional ethics committee, as previously described [27,32]. The DSS from which the GBM reference database is based upon is available from previous reports by [13] us together with the additional files presented in this study.…”